title: Photoreceptor avascular privilege is shielded by soluble VEGF receptor-1.
abstract: Optimal phototransduction requires separation of the avascular photoreceptor layer from the adjacent vascularized inner retina and choroid. Breakdown of peri-photoreceptor vascular demarcation leads to retinal angiomatous proliferation or choroidal neovascularization, two variants of vascular invasion of the photoreceptor layer in age-related macular degeneration (AMD), the leading cause of irreversible blindness in industrialized nations. Here we show that sFLT-1, an endogenous inhibitor of vascular endothelial growth factor A (VEGF-A), is synthesized by photoreceptors and retinal pigment epithelium (RPE), and is decreased in human AMD. Suppression of sFLT-1 by antibodies, adeno-associated virus-mediated RNA interference, or Cre/lox-mediated gene ablation either in the photoreceptor layer or RPE frees VEGF-A and abolishes photoreceptor avascularity. These findings help explain the vascular zoning of the retina, which is critical for vision, and advance two transgenic murine models of AMD with spontaneous vascular invasion early in life. DOI:http://dx.doi.org/10.7554/eLife.00324.001.
authors.affiliation: Moran Eye Center , University of Utah , Salt Lake City , United States ; Department of Ophthalmology , The 306th Hospital of PLA , Beijing , China.
authors.forename: Ling
authors.initials: L
authors.lastname: Luo
authors.forename: Hironori
authors.initials: H
authors.lastname: Uehara
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Das
authors.forename: Thomas
authors.initials: T
authors.lastname: Olsen
authors.forename: Derick
authors.initials: D
authors.lastname: Holt
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Simonis
authors.forename: Kyle
authors.initials: K
authors.lastname: Jackman
authors.forename: Nirbhai
authors.initials: N
authors.lastname: Singh
authors.forename: Tadashi R
authors.initials: TR
authors.lastname: Miya
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Faisal
authors.initials: F
authors.lastname: Ahmed
authors.forename: Ana
authors.initials: A
authors.lastname: Bastos-Carvalho
authors.forename: Yun Zheng
authors.initials: YZ
authors.lastname: Le
authors.forename: Christina
authors.initials: C
authors.lastname: Mamalis
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Judit
authors.initials: J
authors.lastname: Baffi
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Lacal
authors.forename: Angela
authors.initials: A
authors.lastname: Orecchia
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.forename: Kim
authors.initials: K
authors.lastname: Young-Hee
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Fu
authors.forename: Leah
authors.initials: L
authors.lastname: Owen
authors.forename: Romulo
authors.initials: R
authors.lastname: Albuquerque
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Kirk
authors.initials: K
authors.lastname: Thomas
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.forename: Kakarla V
authors.initials: KV
authors.lastname: Chalam
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grisanti
authors.forename: David J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016022:Case-Control Studies; D020256:Choroidal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014785:Vision, Ocular
chemical_list: D000906:Antibodies; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Human; Mouse; age-related macular degeneration; photoreceptor metabolism; retinal vasculature; soluble VEGF receptor-1; transgenic model; vascular demarcation